Celedon Gonzales

Robust Central Reduction of Amyloid-β in Humans with an Orally Available, Non-Peptidic β-Secretase Inhibitor

According to the amyloid cascade hypothesis, cerebral deposition of amyloid-β peptide (Aβ) is critical for Alzheimers disease (AD) pathogenesis. Aβ generation is initiated when β-secretase (BACE1) cleaves the amyloid precursor protein. For more than a decade, BACE1 has been a prime target for designing drugs to prevent or treat AD. However, development of such agents has turned out to be extremely challenging, with major hurdles in cell penetration, oral bioavailability/metabolic clearance, and brain access. Using a fragment-based chemistry strategy, we have generated LY2811376 [(S)-4-(2,4-difluoro-5-pyrimidin-5-yl-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]thiazin-2-ylamine], the first orally available non-peptidic BACE1 inhibitor that produces profound Aβ-lowering effects in animals. The biomarker changes obtained in preclinical animal models translate into man at doses of LY2811376 that were safe and well tolerated in healthy volunteers. Prominent and long-lasting Aβ reductions in lumbar CSF were measured after oral dosing of 30 or 90 mg of LY2811376. This represents the first translation of BACE1-driven biomarker changes in CNS from preclinical animal models to man. Because of toxicology findings identified in longer-term preclinical studies, this compound is no longer progressing in clinical development. However, BACE1 remains a viable target because the adverse effects reported here were recapitulated in LY2811376-treated BACE1 KO mice and thus are unrelated to BACE1 inhibition. The magnitude and duration of central Aβ reduction obtainable with BACE1 inhibition positions this protease as a tractable small-molecule target through which to test the amyloid hypothesis in man.

Safety, tolerability, and changes in amyloid β concentrations after administration of a γ-secretase inhibitor in volunteers

Amyloid β (Aβ) may play a central role in the pathogenesis of Alzheimer disease. A functional γ-secretase inhibitor, LY450139, was developed that inhibits Aβ formation in whole cell assays, transgenic mice, and beagle dogs. The authors wished to determine the safety and tolerability of this drug, and the reduction of Aβ in plasma and cerebrospinal fluid (CSF) after multiple doses. Volunteer subjects (N = 37) were studied using doses from 5 to 50 mg/day given for 14 days. Plasma and CSF concentrations of LY450139, Aβ1-40 and Aβ1-X (“Aβtotal”) were determined, and safety and tolerability were assessed. The plasma half-life of LY450139 was approximately 2.5 hours. Pharmacokinetic analyses showed a linear relationship between dose and plasma concentrations, with a Cmax of 828 ± 19.2 ng/mL after a 50-mg dose. Plasma Aβ concentrations decreased in a dose-dependent manner over a 6-hour interval following drug administration, with a maximum decrease of approximately 40% relative to baseline. After returning to baseline, Aβ concentrations were transiently increased. CSF Aβ concentrations were unchanged. Adverse events reported by subjects taking 5-mg, 20-mg, or 40-mg doses were similar to those reported by subjects taking placebo. Two of 7 subjects taking 50 mg/day experienced adverse events that may have been drug related. In this phase 1 volunteer study, reported adverse events after taking LY450139 were manageable. A dose-dependent reduction in plasma Aβ was demonstrated, and changes in plasma Aβ concentrations were temporally related to the pharmacokinetic characteristics of LY450139.

Safety and biomarker effects of solanezumab in patients with Alzheimer’s disease

To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of 12 weekly infusions of solanezumab, an anti‐β‐amyloid (Aβ) antibody, in patients with mild‐to‐moderate Alzheimers disease. Cognitive measures were also obtained.

Safety, Tolerability, and Effects on Plasma and Cerebrospinal Fluid Amyloid-β After Inhibition of γ-Secretase

Objectives: &ggr;-Secretase inhibitors may be useful as disease-modifying drugs for the treatment of Alzheimer disease. LY450139 is a &ggr;-secretase inhibitor currently in clinical development, with doses being optimized through the use of biomarkers. Methods: To further characterize biomarker responses to LY450139, single oral doses of 60, 100, or 140 mg were administered to volunteers without neuropsychiatric disease. Extensive safety assessments were obtained along with measures of changes in amyloid-&bgr; (A&bgr;) in plasma and cerebrospinal fluid (CSF). A measure of the change in plasma A&bgr;1-40 was derived (area above the curve), which was determined by both the magnitude and duration of A&bgr;1-40 reduction. Results: A total of 31 subjects (ages 49-53 years, 19 men) were enrolled. With the possible exception of headache, no clinically significant adverse events or laboratory changes were observed. A dose-proportional increase in drug exposure was present in plasma and in CSF. A dose-dependent change in plasma A&bgr;1-40 area above the curve was also demonstrated. Using the 140-mg dose, a maximum 72.6% reduction in plasma A&bgr;1-40 was demonstrated that did not return to baseline for more than 12 hours. Cerebrospinal fluid concentrations of A&bgr; were unchanged 4 hours after drug administration. Conclusions: These data show that single doses of LY450139 up to 140 mg are accompanied by a dose-dependent plasma A&bgr; response. No response in CSF A&bgr; was apparent 4 hours after dosing.

Safety and Changes in Plasma and Cerebrospinal Fluid Amyloid β After a Single Administration of an Amyloid β Monoclonal Antibody in Subjects With Alzheimer Disease

Objectives:Active and passive immunization strategies have been suggested as possible options for the treatment of Alzheimer disease (AD). LY2062430 (solanezumab) is a humanized monoclonal antibody being studied as a putative disease-modifying treatment of AD. Methods:Patients with mild to moderate AD were screened and selected for inclusion. Initial screening was performed for 54 subjects, and 29 of these underwent additional screening; after this second screening, a total of 19 subjects were included. Single doses of solanezumab using 0.5, 1.5, 4.0, and 10.0 mg/kg were administered. Safety assessments included gadolinium-enhanced magnetic resonance imaging of the brain and cerebrospinal fluid (CSF) analyses at baseline and 21 days after dosing. Plasma and CSF concentrations of solanezumab and amyloid &bgr; (A&bgr;) and cognitive evaluations were obtained. Results:Administration of solanezumab was generally well tolerated except that mild self-limited symptoms consistent with infusion reactions occurred for 2 of 4 subjects given 10 mg/kg. No evidence of meningoencephalitis, microhemorrhage, or vasogenic edema was present based on magnetic resonance image and CSF analyses. A substantial dose-dependent increase in total (bound plus unbound) A&bgr; was demonstrated in plasma; CSF total A&bgr; also increased. No changes in cognitive scores occurred. Conclusions:A single dose of solanezumab was generally well tolerated, although infusion reactions similar to those seen with administration of other proteins may occur with higher doses. A dose-dependent change in plasma and CSF A&bgr; was observed, although changes in cognitive scores were not noted. Further studies of solanezumab for the treatment of AD are warranted.

The Potent BACE1 Inhibitor LY2886721 Elicits Robust Central Aβ Pharmacodynamic Responses in Mice, Dogs, and Humans

BACE1 is a key protease controlling the formation of amyloid β, a peptide hypothesized to play a significant role in the pathogenesis of Alzheimers disease (AD). Therefore, the development of potent and selective inhibitors of BACE1 has been a focus of many drug discovery efforts in academia and industry. Herein, we report the nonclinical and early clinical development of LY2886721, a BACE1 active site inhibitor that reached phase 2 clinical trials in AD. LY2886721 has high selectivity against key off-target proteases, which efficiently translates in vitro activity into robust in vivo amyloid β lowering in nonclinical animal models. Similar potent and persistent amyloid β lowering was observed in plasma and lumbar CSF when single and multiple doses of LY2886721 were administered to healthy human subjects. Collectively, these data add support for BACE1 inhibition as an effective means of amyloid lowering and as an attractive target for potential disease modification therapy in AD.

QT effects of duloxetine at supratherapeutic doses: A placebo and positive controlled study

Background: The electrophysiological effects of duloxetine at supratherapeutic exposures were evaluated to ensure compliance with regulatory criteria and to assess the QT prolongation potential. Methods: Electrocardiograms were collected in a multicenter, double-blind, randomized, placebo-controlled, crossover study that enrolled 117 healthy female subjects aged 19 to 74 years. Duloxetine dosages escalated from 60 mg twice daily to 200 mg twice daily; a single moxifloxacin 400 mg dose was used as a positive control. Data were analyzed using 3 QT interval correction methods: mixed-effect analysis of covariance model with RR interval change from baseline as the covariate, the QT Fridericias correction method, and the individual QT correction method. Concentrations of duloxetine and its 2 major metabolites were measured. Results: Compared with placebo, the mean change from baseline in QTc decreased with duloxetine 200 mg twice daily. The upper limits of the 2-sided 90% confidence intervals for duloxetine vs. placebo were <0 msec at each time point by any correction method. No subject had absolute QT Fridericias correction values >445 msec with duloxetine, and the change in QT Fridericias correction from baseline with duloxetine did not exceed 36 msec. No relationship was detected between QTc change and plasma concentrations of duloxetine or its metabolites even though average duloxetine concentrations ranged to more than 5 times those achieved at therapeutic doses. Moxifloxacin significantly prolonged QTc at all time points, regardless of correction method. Conclusions: Duloxetine does not affect ventricular repolarization as assessed by both mean changes and outliers in QT corrected by any method.

Safety, tolerability, and pharmacokinetic evaluation of single- and multiple-ascending doses of a novel kappa opioid receptor antagonist LY2456302 and drug interaction with ethanol in healthy subjects.

Accumulating evidence indicates that selective antagonism of kappa opioid receptors may provide therapeutic benefit in the treatment of major depressive disorder, anxiety disorders, and substance use disorders. LY2456302 is a high‐affinity, selective kappa opioid antagonist that demonstrates >30‐fold functional selectivity over mu and delta opioid receptors. The safety, tolerability, and pharmacokinetics (PK) of LY2456302 were investigated following single oral doses (2–60 mg), multiple oral doses (2, 10, and 35 mg), and when co‐administered with ethanol. Plasma concentrations of LY2456302 were measured by liquid chromatography‐tandem mass spectrometry method. Safety analyses were conducted on all enrolled subjects. LY2456302 doses were well‐tolerated with no clinically significant findings. No safety concerns were seen on co‐administration with ethanol. No evidence for an interaction between LY2456302 and ethanol on cognitive‐motor performance was detected. LY2456302 displayed rapid oral absorption and a terminal half‐life of approximately 30–40 hours. Plasma exposure of LY2456302 increased proportionally with increasing doses and reached steady state after 6–8 days of once‐daily dosing. Steady‐state PK of LY2456302 were not affected by coadministration of a single dose of ethanol. No clinically important changes in maximum concentration (Cmax) or AUC of ethanol (in the presence of LY2456302) were observed.

The effects of supratherapeutic doses of duloxetine on blood pressure and pulse rate.

The effects of supratherapeutic dosages of duloxetine, a serotonin and norepinephrine reuptake inhibitor, on blood pressure and pulse rate were assessed in a multicenter, double-blind, randomized, placebo-controlled, crossover study in 117 healthy women aged 19 to 74 years. Dosages were escalated from 60 mg twice daily (BID) to 200 mg BID over 16 days. Vital signs were monitored at baseline, before morning dosing, and sequentially at steady state. Duloxetine produced increases in supine systolic and diastolic blood pressures, which reached maximums of ~12 mm Hg and ~7 mm Hg above baseline, respectively, during dosing at 120 mg BID and then stabilized. Supine pulse rate increased gradually with dose, reaching 10 to 12 bpm above baseline after 4 days of dosing at 200 mg BID. Duloxetine caused changes in orthostatic blood pressures and pulse rate that reached plateau values after 3 to 4 days of dosing at 160 mg BID and were generally not associated with subjectively reported orthostatic-related adverse events. All vital signs normalized by 1 to 2 days after study drug discontinuation. Prehypertensive subjects may become hypertensive upon initial duloxetine dosing, but this can be predicted from predose blood pressure. Short-term supratherapeutic duloxetine dosages up to 200 mg BID are not well tolerated but are generally not associated with severe, clinically important adverse events. Overall, the types of adverse events reported in this study were similar to those in other studies of duloxetine in healthy subjects.

Effects of Varying Degrees of Renal Impairment on the Pharmacokinetics of Duloxetine

BackgroundDuloxetine is indicated for patients with a variety of conditions, and some of these patients may have mild to moderate degrees of renal impairment. Renal impairment may affect the pharmacokinetics of a drug by causing changes in absorption, distribution, protein binding, renal excretion or nonrenal clearance. As duloxetine is highly bound to plasma proteins and its metabolites are renally excreted, it is prudent to evaluate the effect of renal insufficiency on exposure to duloxetine and its metabolites in the systemic circulation.ObjectiveThe aim of this study was to evaluate the effects of varying degrees of renal impairment on duloxetine pharmacokinetics in a single-dose phase I study and using pooled steady-state pharmacokinetic data from phase II/III trials.MethodsIn the phase I study, a single oral dose of duloxetine 60 mg was given to 12 subjects with end-stage renal disease (ESRD) and 12 matched healthy control subjects. In the phase II/III trials (n = 463 patients), duloxetine 20–60 mg was given as once- or twice-daily doses. Duloxetine and metabolite concentrations in plasma were determined using liquid chromatography with tandem mass spectrometry. Noncompartmental methods (phase I: duloxetine and its metabolites) and population modelling methods (phase II/III: duloxetine) were used to analyse the pharmacokinetic data.ResultsThe maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) of duloxetine were ∼2-fold higher in subjects with ESRD than in healthy subjects, which appeared to reflect an increase in oral bioavailability. The Cmax and AUC of two major inactive conjugated metabolites were as much as 2- and 9-fold higher, respectively, reflecting reduced renal clearance of these metabolites. Population pharmacokinetic results indicated that mild or moderate renal impairment, assessed by creatinine clearance (CLCR) calculated according to the Cockcroft-Gault formula, did not have a statistically significant effect on pharmacokinetic parameters of duloxetine. Values for the apparent total body clearance of duloxetine from plasma after oral administration (CL/F) in subjects with ESRD were similar to CL/F values in patients with normal renal function or with mild or moderate renal impairment.ConclusionDose adjustments for duloxetine are not necessary for patients with mild or moderate renal impairment (CLcr ≥30 mL/min). For patients with ESRD or severe renal impairment (CLcr <30 mL/min), exposures of duloxetine and its metabolites are expected to increase; therefore, duloxetine is not generally recommended for these patients.